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Abstract p95HER2 isoform is a truncated form of HER2 that retains the C terminal domain but lacks an N terminal trastuzumab binding site. From 2014 to 2016, we assessed the expression of p95HER2 expression in 59 HER2‐positive breast cancer patients from FUSCC. The median follow‐up was 54 months. In our study, 19 patients (32.2%) were p95HER2 positive. p95HER2‐positive expression rate is higher in premenopausal patients than in postmenopausal patients (68.4% vs. 31.6%, P = .026). p95HER2 positive was found more in premenopausal patients and was associated with worse DFS (hazard ratio, 2.21; 95% CI, 1.06–4.61; P = .034), indicating that p95HER2 expression tends to be a more aggressive isoform type of HER2‐positive breast cancer.

Abstract This study aimed to develop a machine learning (ML)-based tool for early and accurate prediction of in-hospital mortality risk in patients with spontaneous intracerebral hemorrhage (sICH) in the intensive care unit (ICU). We did a retrospective study in our study and identified cases of sICH from the MIMIC IV (n = 1486) and Zhejiang Hospital databases (n = 110). The model was constructed using features selected through LASSO regression. Among five well-known models, the selection of the best model was based on the area under the curve (AUC) in the validation cohort. We further analyzed calibration and decision curves to assess prediction results and visualized the impact of each variable on the model through SHapley Additive exPlanations. To facilitate accessibility, we also created a visual online calculation page for the model. The XGBoost exhibited high accuracy in both internal validation (AUC = 0.907) and external validation (AUC = 0.787) sets. Calibration curve and decision curve analyses showed that the model had no significant bias as well as being useful for supporting clinical decisions. XGBoost is an effective algorithm for predicting in-hospital mortality in patients with sICH, indicating its potential significance in the development of early warning systems.

Abstract Purpose As a minimally invasive procedure, laser hemorrhoidoplasty (LHP) can not only relieve the symptoms of hemorrhoids, but also protect the anal cushion structure. This study aimed to investigate the clinical efficacy of LHP in the treatment of grade II hemorrhoids. Methods A total of 70 patients with grade II hemorrhoids were randomly assigned to receive LHP or Rubber Band Ligation (RBL) (n = 35 per group) in 2019 from a single center. The postoperative pain, bleeding, feeling of anal distension(local falling, swelling, foreign body sensation, stool) and postoperative recurrence rate were compared between the two groups. Results The postoperative pain, bleeding, and feeling of anal distension in the LHP group were improved significantly as compared with the RBL group within 2 weeks after surgery (P 0.05). The patients in LHP group took less time to return to normal activities (P

Objective Breast-conserving therapy (BCT) includes breast-conserving surgery (BCS) combined with radiation therapy (RT). RT plays a crucial role in improving the prognosis of patients who undergo BCS. However, obesity is a potential risk factor for resistance to radiation. The aim of this study was to evaluate any difference in the long-term prognosis of patients with early stage breast cancer and obesity treated with BCT or total mastectomy (TM).Design, setting and participants This was a retrospective cohort study involving 1125 patients diagnosed with early stage breast cancer and obesity at the Shanghai Cancer Center of Fudan University from 2013 to 2016.Outcome measures Obesity in the Chinese population was defined as a body mass index ≥28 kg/m2. Surgical options included BCT and TM. The primary survival outcomes were overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS). Inverse probability of treatment weighting (IPTW) was used to control for the impact of confounding factors on prognosis.Results The median follow-up times in the BCT group and TM group without postoperative RT were 51.1 months (IQR of 40.6–68.1 months) and 61.8 months (IQR of 46.5–76.7 months), respectively. After IPTW, the baseline data were balanced. Compared with those in the TM cohort, patients in the whole IPTW cohort in the BCT cohort had worse DFS (HR 4.280, 95% CI 2.180 to 8.400; p

Summary: Background: Toripalimab, a novel PD-1 antibody, is approved for treatment of multiple solid tumors; however, its neoadjuvant use with chemotherapy for triple-negative breast cancer (TNBC) remains unevaluated. Additionally, induction chemotherapy followed by de-escalation of neoadjuvant immunotherapy remains underexplored. Therefore, we conducted a phase II trial investigating a novel neoadjuvant chemoimmunotherapy regimen including de-escalation of immunotherapy for early-stage TNBC. Methods: Chemotherapy and anti-PD-1 therapy were sequentially administered in a neoadjuvant setting to female patients with histologically confirmed stage II–III TNBC between June 9, 2020, and March 24, 2022. Patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks, followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was total pathological complete response (tpCR; ypT0/is ypN0). Key secondary endpoints included breast pCR (bpCR; ypT0/is), event-free survival and biomarker analysis. Safety was also assessed. This study was registered with ClinicalTrials.gov (NCT04418154). Findings: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 completed treatment without progression and subsequently underwent surgery. The percentages of patients with a tpCR and bpCR were 39 of 70 (55.7%, 95% confidence interval [CI]: 43.3–67.6) and 41 of 70 (58.6%, 95% CI 46.2–70.2), respectively. Sixteen (22.9%) patients experienced grade ≥3 adverse events (AEs), frequently neutropenia (12, 17.1%) and leukopenia (11, 15.7%). The most common immune-related AE was hypothyroidism (5, 7.1%, all grade 1–2). Interpretation: Including 12 weeks of toripalimab in neoadjuvant chemotherapy conferred encouraging activity and manageable toxicity in patients with early TNBC, and this regimen warrants further investigation. Funding: National Natural Science Foundation of China, Junshi Biosciences, and Jiangsu Hengrui Pharmaceuticals.

Background: Breast cancer (BC) poses a global threat, with HER2-positive BC being a particularly hazardous subtype. Despite the promise shown by neoadjuvant therapy (NAT) in improving prognosis, resistance in HER2-positive BC persists despite emerging targeted therapies. The objective of this study is to identify markers that promote therapeutic sensitivity and unravel the underlying mechanisms. Methods: We conducted an analysis of 86 HER2-positive BC biopsy samples pre-NAT using RNA-seq. Validation was carried out using TCGA, Kaplan‒Meier Plotter, and Oncomine databases. Phenotype verification utilized IC50 assays, and prognostic validation involved IHC on tissue microarrays. RNA-seq was performed on wild-type/DUSP4-KO cells, while RT‒qPCR assessed ROS pathway regulation. Mechanistic insights were obtained through IP and MS assays. Results: Our findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER2-positive BC. Moreover, DUSP4 hinders G6PD activity via ALDOB dephosphorylation, with a noteworthy association with heightened ROS levels. Conclusions: In summary, our study unveils a metabolic reprogramming paradigm in BC, highlighting DUSP4′s role in enhancing therapeutic sensitivity in HER2-positive BC cells. DUSP4 interacts with ALDOB, inhibiting G6PD activity and the ROS pathway, establishing it as an independent prognostic predictor for HER2-positive BC patients.

Abstract Background Sentinel lymph node biopsy (SLNB) is a common choice for axillary surgery in patients with early‐stage breast cancer (BC) who have clinically negative lymph nodes. Most research indicates that obesity is a prognostic factor for BC patients, but studies assessing its association with the rate of positive sentinel lymph nodes (SLN) and the prognosis of patients with early BC undergoing SLNB are limited. Methods Between 2013 and 2016, 7062 early‐stage BC patients from the Shanghai Cancer Center of Fudan University were included. Based on the Chinese Body Mass Index (BMI) classification standards, the patients were divided into three groups as follows: normal weight, overweight, and obese. Propensity score matching analysis was used to balance the baseline characteristics of the participants. Logistic regression analysis was used to determine the association between obesity and positive SLN rate. Cox regression analysis was used to investigate whether obesity was an independent prognostic factor for early‐stage BC patients who had undergone SLNB. Results No significant association was observed between obesity and positive SLN rate in early‐stage BC patients who had undergone SLNB. However, multivariate analysis revealed that compared to patients with normal BMI, the overall survival (hazard ratio (HR) 2.240, 95% confidence interval (CI) 1.27–3.95, p = 0.005) and disease‐free survival (HR 1.750, 95% CI 1.16–2.62, p = 0.007) were poorer in patients with high BMI. Conclusion Obesity is an independent prognostic factor for early‐stage BC patients who undergo SLNB; however, it does not affect the positive SLN rate.

Ammonium (NH4+) plays a crucial role in the reproductive processes of key biotic groups in aquatic ecosystems—bivalves. This study aims to elucidate the effects of three different ammonium ion concentrations on sperm vitality, swimming kinematics, and morphology of Mimachlamys nobilis, Pinctada fucata martensii, and Saccostrea mordax. The results indicate that the sperm vitality and motility rates of M.nobilis and S. mordax are inversely proportional to the ammonium concentration, especially in the treatment group with an ammonium concentration of 3 mmol/L, where the decrease in sperm vitality and motility is most significant. In contrast, the sperm of P. fucata martensii reacted differently to increasing ammonium concentrations. After the addition of 2 mmol/L of ammonium, the sperm vitality and motility of P. fucata martensii reached a peak, showing a significant stimulatory effect. Additionally, as the ammonium concentration increased, the curling of the sperm flagella in M.nobilis and S. mordax increased. However, sperm flagella curling in P. fucata martensii showed no change compared to the control group. This study provides insights into the effects of ammonium concentrations on the sperm vitality and motility of three marine bivalve species and highlights the importance of sperm flagella curling as a factor affecting sperm.

Background: Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. Objectives: TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I–III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Methods and design: Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator’s choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. Ethics: TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. Discussion: TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. Trial registration: ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

Background: With our growing insight into the molecular heterogeneity and biological characteristics of breast cancer, individualized treatment is the future of cancer treatment. In this prospective Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study – neoadjuvant therapy (FASCINATE-N) trial, we classify breast cancer patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. Methods and design: The FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. After enrollment, patients will first be divided into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)−, HER2+, and HR−/HER2−. The HR+/HER2− patients are further stratified using fusion and clustering of similarity network fusion (SNF) algorithm into four subtypes; HER2+ patients are divided into HR+/HER2+ and HR−/HER2+ subtypes; and HR−/HER2− patients are stratified using the Fudan University Shanghai Cancer Center classification. For the assignment of drugs to patients, Bayesian methods of adaptive randomization will be used. The primary endpoint is pathological complete response rate; secondary endpoints include 3-year invasive disease-free survival, overall response rate, and toxicities according to common terminology criteria for adverse events (CTCAE) scale version 4.0 and the ratio of patients with complete cell cycle arrest (Ki67 < 2.7%) in HR+/HER2+ breast cancer. Discussion: The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets, and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients. Trial registration: ClinicalTrials.gov identifier: NCT05582499 ( https://classic.clinicaltrials.gov/ct2/show/NCT05582499 ).

Abstract Purpose The function of stanniocalcin‐1 (STC‐1) in the oncogenesis and progression of tumors has been extensively studied. The purpose of this study was to investigate the relationship between secreted STC‐1 and prognosis in patients with breast cancer (BC) and to determine whether STC‐1 could be a key prognostic factor in BC. Methods The STC‐1 level was measured by ELISA and clinical data from 1210 female patients with BC were used to develop and validate nomograms. We then verified the models through the plotting of ROC curves and calibration curves, calculating the C‐index, and performing decision curve analyses (DCA). Results The level of STC‐1 in the peripheral plasma was significantly correlated with the T stage, N stage, clinical stage, grade, hormone receptors, HER‐2 status, and tumor subtype. Cox regression analyses revealed that estrogen receptor(ER) status, N stage, and STC‐1 level were risk factors for overall survival (OS), whereas T stage, N stage, and STC‐1 level were independent prognostic factors for distant disease‐free survival (DDFS) and disease‐free survival (DFS). Both the ROC curve and the C‐index confirmed the high resolution of these models, while the DCA identified the feasibility of their practical application. In addition, the calibration curves indicated good consistency between the predicted and actual survival rates. Conclusion Nomograms were created based on STC‐1 levels for 3‐, 5‐, and 7‐year OS, DDFS, and DFS of patients with BC respectively. As a key prognostic factor for BC, peripheral blood STC‐1 level can be used clinically as a liquid biopsy indicator.

Abstract Background Metastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanisms are still largely unknown. Methods The transcriptional and posttranscriptional processing of LINC00478-associated cytoplasmic RNA (LacRNA) was determined by RT-qPCR, semiquantitative PCR and 5′/3′ RACE. Paired-guide CRISPR/cas9 and CRISPR/dead-Cas9 systems was used to knock out or activate the expression of LacRNA. Cell migration and invasion assay was performed to confirm the phenotype of LacRNA. Tail vein model and mammary fat pad model were used for in vivo study. The LacRNA-PHB2-cMyc axis were screened and validated by RNA pulldown, mass spectrometry, RNA immunoprecipitation and RNA-seq assays. Results Here, we identified a novel cytoplasmic lncRNA, LacRNA (LINC00478-associated cytoplasmic RNA), derived from nucleus-located lncRNA LINC00478. The nascent transcript of LINC00478 full-length (LINC00478_FL) was cleaved and polyadenylated, simultaneously yielding 5′ ends stable expressing LacRNA, which is released into the cytoplasm, and long 3′ ends of nuclear-retained lncRNA. LINC00478_3′RNA was rapidly degraded. LacRNA significantly inhibited breast cancer invasion and metastasis in vitro and in vivo. Mechanistically, LacRNA physically interacted with the PHB domain of PHB2 through its 61–140-nt region. This specific binding affected the formation of the autophagy degradation complex of PHB2 and LC3, delaying the degradation of the PHB2 protein. Unexpectedly, LacRNA specifically interacted with PHB2, recruited c-Myc and promoted c-Myc ubiquitination and degradation. The negatively regulation of Myc signaling ultimately inhibited breast cancer metastasis. Furthermore, LacRNA and LacRNA-mediated c-Myc signaling downregulation are significantly associated with good clinical outcomes, take advantage of these factors we constructed a prognostic predict model. Conclusion Therefore, our findings propose LacRNA as a potential prognostic biomarker and a new therapeutic strategy.

Abstract Background Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. Methods In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. Results Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. Conclusions The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. Trial registration ClinicalTrials.gov, NCT03588091

Purpose: Changes in biological features and functional status make management decisions in older women with primary breast cancer complicated. We aimed to provide an overview of the clinicopathological characteristics and survival outcomes of older breast cancer patients based on the current treatment strategies. Methods: Female patients diagnosed with primary invasive breast cancer at Fudan University Shanghai Cancer Centre from 2008 to 2016 were included. Patients were divided into a younger group (

BackgroundThe latissimus dorsi flap (LDF) is the most commonly used autologous flap for breast reconstruction (BR) in China. We conducted this study to explore the current status of BR using LDF with/without implants.MethodsThis study was a single-center retrospective study that included breast tumor patients who underwent LDF breast reconstruction at Fudan University Shanghai Cancer Center (FUSCC) between 2000 and 2021.ResultsWe analyzed 4918 patients who underwent postmastectomy BR, including 1730 patients (35.2%) with autologous flaps. LDF was used for BR in 1093 (22.2%) patients, and an abdominal flap was used in 637 (13.0%) patients. The proportion of LDFs used in autologous BR patients decreased each year and dropped to approximately 65.0% after 2013 due to the increased use of abdominal flaps. Among these patients, 609 underwent extended LDF (ELDF) BR, 455 underwent LDF BR with implants, and 30 received a LDF as a salvage flap due to previous flap or implant failure. Patients who underwent ELDF reconstruction were older and had a higher BMI than those who received a LDF with implants. There was no significant difference in the mean postoperative hospital stay, neoadjuvant chemotherapy rates, or adjuvant radiotherapy rates between the two groups. Major complications requiring surgical intervention occurred in 25 patients (2.29%). There was no significant difference in the incidence of major complications between the two groups (P=0.542).ConclusionsLDF breast reconstruction is a well-developed and safe procedure. The duration of postoperative hospitalization nor the incidence of major complications was affected by implant use.

BackgroundIn-stent restenosis (ISR) is an adverse and notable event in the treatment of intracranial atherosclerotic stenosis (ICAS) with percutaneous transluminal angioplasty and stenting (PTAS). The incidence and contributing factors have not been fully defined. This study was performed to evaluate factors associated with ISR after PTAS.Data sourceWe identified studies on ISR after PTAS from an electronic search of articles in PubMed, Ovid MEDLINE, and the Cochrane Central Database (dated up to July 2022).ResultsA total of 19 studies, including 452 cases of ISR after 2,047 PTAS, were included in the meta-analysis. The pooled incidence rate of in-stent restenosis was 22.08%. ISR was more likely to occur in patients with coronary artery disease (OR = 1.686; 95% CI: 1.242–2.288; p = 0.0008), dissection (OR = 6.293; 95% CI: 3.883–10.197; p < 0.0001), and higher residual stenosis (WMD = 3.227; 95% CI: 0.142–6.311; p = 0.0404). Patients treated with Wingspan stents had a significantly higher ISR rate than those treated with Enterprise stents (29.78% vs. 14.83%; p < 0.0001).ConclusionsThe present study provides the current estimates of the robust effects of some risk factors for in-stent restenosis in intracranial atherosclerotic stenosis. The Enterprise stent had advantages compared with the Wingspan stent for ISR. The significant risk factors for ISR were coronary artery disease, dissection, and high residual stenosis. Local anesthesia was a suspected factor associated with ISR.

Although targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer has significantly prolonged survival time and improved patients’ quality of life, drug resistance has gradually emerged. This study explored the mechanisms underlying the effect of the motor neuron and pancreatic homeobox 1 (MNX1) genes on drug sensitivity in HER2-positive breast cancer. From July 2017 to 2018, core needle biopsies of HER2-positive breast cancer were collected from patients who received paclitaxel, carboplatin, and trastuzumab neoadjuvant therapy at our center. Based on treatment efficacy, 81 patients were divided into pathological complete response (pCR) and non-pCR groups. High-throughput RNA sequencing results were analyzed along with the GSE181574 dataset. MNX1 was significantly upregulated in the pCR group compared with the non-pCR group in both sequencing datasets, suggesting that MNX1 might be correlated with drug sensitivity in HER2-positive breast cancer. Meanwhile, tissue array results revealed that high MNX1 expression corresponded to a good prognosis. In vitro functional tests showed that upregulation of MNX1 significantly increased the sensitivity of HER2-positive breast cancer cells to lapatinib and pyrotinib. In conclusion, MNX1 may serve as a prognostic marker for patients with HER2-positive breast cancer, and its expression may facilitate clinical screening of patients sensitive to anti-HER2-targeted therapy.

Platinum agents, such as carboplatin and cisplatin, have been recommended in combination with gemcitabine for the treatment of metastatic triple negative breast cancer (TNBC). Here the authors report the results of a randomized phase 3 trial to compare the efficacy of first-line nab-paclitaxel/cisplatin to gemcitabine/cisplatin in patients with TNBC.

Purpose: Neoadjuvant therapy (NAT) is considered the standard of care for patients with HER2-positive breast cancer (BC). However, there is no proven survival benefit of NAT compared to adjuvant therapy for the survival of patients with early-stage HER2-positive BC. This study aimed to compare the prognosis of HER2-positive BC patients treated with NAT to that of patients treated with adjuvant therapy. Methods: This was a single-center real-world retrospective study. This study analyzed the disease-free survival (DFS) and overall survival (OS) of 538 HER2-positive BC patients treated with neoadjuvant therapy and 2684 patients treated with adjuvant therapy at Fudan University Shanghai Cancer Center (FUSCC) between 2012 and 2016. Patients with a clinical tumor size (cT) ≤5 cm or >5 cm were matched using the propensity score matching (PSM) method to prevent selection bias. Results: After PSM, among patients with cT ≤ 5 cm, there was no significant difference in DFS (P = 0.08) or OS (P = 0.11) between the two groups. The analysis of survival outcomes of patients treated with neoadjuvant and adjuvant therapy in the different chemotherapy subgroups yielded consistent results. According to multivariate analysis, lymph node status and response to NAT showed independent prognostic value for OS and DFS. Among patients with cT > 5 cm, the DFS (P = 0.25) and OS (P = 0.57) of patients treated with NAT were similar to those of patients treated with adjuvant therapy after PSM. Conclusion: We confirmed the equivalent effects of adjuvant therapy and NAT in HER2-positive BC patients. Neoadjuvant therapy should be used for patients with HER2-positive BC.

Estrogen receptor‐positive and human epidermal growth factor receptor 2‐negative (ER+HER2−) breast cancer accounts for ~ 60–70% of all cases of invasive breast carcinoma. High‐grade ER+HER2− tumors respond poorly to endocrine therapy. In this study, we systematically analyzed clinical and multi‐omics data to find potential strategies for personalized therapy of patients with high‐grade ER+HER2− disease. Six different cohorts were analyzed, for which multi‐omics data were available. Grade III ER+HER2− cases harbored higher proportions of large tumor size (> 5 cm), lymph node metastasis, chemotherapy use, and luminal B subtypes defined by PAM50, as compared with grade I/II tumors. DNA methylation (HM450) data and methylation‐specific PCR indicated that the cg18629132 locus in the MKI67 promoter was hypermethylated in grade I/II cases and normal tissue, but hypomethylated in grade III cases or triple‐negative breast cancer, resulting in higher expression of MKI67. Mutations in ESR1 and TP53 were detected in post‐endocrine treatment metastatic samples at a higher rate than in treatment‐naive tumors in grade III cases. We identified 42 and 20 focal copy number events in nonmetastatic and metastatic high‐grade ER+HER2− cases, respectively, with either MYC or MDM2 amplification representing an independent prognostic event in grade III cases. Transcriptional profiling within grade III tumors highlighted ER signaling downregulation and upregulation of immune‐related pathways in non‐luminal‐like tumors defined by PAM50. Recursive partitioning analysis was employed to construct a decision tree of an endocrine‐resistant subgroup (GATA3‐negative and AGR‐negative) of two genes that was validated by immunohistochemistry in a Chinese cohort. All together, these data suggest that grade III ER+HER2− tumors have distinct clinical and molecular characteristics compared with low‐grade tumors, particularly in cases with non‐luminal‐like biology. Due to the dismal prognosis in this group, clinical trials are warranted to test the efficacy of potential novel therapies.

Background: Fractional flow reserve is widely used for the functional evaluation of coronary artery stenosis. Some studies have similarly used the translesional pressure ratio measurements for the functional evaluation of intracranial atherosclerotic stenosis. In this paper, we aimed to investigate the relationship between pressure ratio and cerebral tissue perfusion by MR perfusion imaging and provided a non-invasive method for evaluating the functional significance of intracranial atherosclerotic stenosis. Methods: A total of 18 consecutive patients with intracranial atherosclerotic stenosis patients including 19 stenotic vessels were recruited. The pressure was measured using a pressure guidewire, the pressure ratio before and after the endovascular intervention was calculated and compared with the severity of diameter stenosis and perfusion-derived MR (the time to maximum tissure residue function (Tmax)). Moreover, the DSA-derived pressure ratio was computed using a novel computational fluid dynamics-based model, termed CFD-PR, and was compared with the actual pressure ratio to assess its diagnostic accuracy. Results: The pressure ratio increased after percutaneous transluminal angioplasty or stenting, while the correlation between pressure ratio and diameter stenosis was not significant. The pressure ratio was negatively correlated with Tmax (r = −0.73, P

Abstract Background Human epidermal growth factor receptor2+ subtype breast cancer has a high degree of malignancy and a poor prognosis. The aim of this study is to develop a prediction model for the human epidermal growth factor receptor2+ subtype (non-luminal) of breast cancer based on the clinical and ultrasound features related with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor2. Methods We collected clinical data and reviewed preoperative ultrasound images of enrolled breast cancers from September 2017 to August 2020. We divided the data into in three groups as follows. Group I: estrogen receptor ± , Group II: progesterone receptor ± and Group III: human epidermal growth factor receptor2 ± . Univariate and multivariate logistic regression analyses were used to analyze the clinical and ultrasound features related with biomarkers among these groups. A model to predict human epidermal growth factor receptor2+ subtype was then developed based on the results of multivariate regression analyses, and the efficacy was evaluated using the area under receiver operating characteristic curve, accuracy, sensitivity, specificity. Results The human epidermal growth factor receptor2+ subtype accounted for 138 cases (11.8%) in the training set and 51 cases (10.1%) in the test set. In the multivariate regression analysis, age ≤ 50 years was an independent predictor of progesterone receptor + (p = 0.007), and posterior enhancement was a negative predictor of progesterone receptor + (p = 0.013) in Group II; palpable axillary lymph node, round, irregular shape and calcifications were independent predictors of the positivity for human epidermal growth factor receptor-2 in Group III (p = 0.001, p = 0.007, p = 0.010, p

Abstract A large number RNAs are enriched and stable in extracellular vesicles (EVs), and they can reflect their tissue origins and are suitable as liquid biopsy markers for cancer diagnosis and treatment efficacy prediction. In this study, we used extracellular vesicle long RNA (exLR) sequencing to characterize the plasma-derived exLRs from 112 breast cancer patients, 19 benign patients and 41 healthy participants. The different exLRs profiling was found between the breast cancer and non-cancer groups. Thus, we constructed a breast cancer diagnostic signature which showed high accuracy with an area under the curve (AUC) of 0.960 in the training cohort and 0.900 in the validation cohort. The signature was able to identify early stage BC (I/II) with an AUC of 0.940. Integrating the signature with breast imaging could increase the diagnosis accuracy for breast cancer patients. Moreover, we enrolled 58 patients who received neoadjuvant treatment and identified an exLR (exMSMO1), which could distinguish pathological complete response (pCR) patients from non-pCR with an AUC of 0.790. Silencing MSMO1 could significantly enhance the sensitivity of MDA-MB-231 cells to paclitaxel and doxorubicin through modulating mTORC1 signaling pathway. This study demonstrated the value of exLR profiling to provide potential biomarkers for early detection and treatment efficacy prediction of breast cancer.

Radiotherapy (RT) is a major modality of postoperative treatment in breast cancer. The maximal standardized value (SUVmax) is 18FDG-PET/CT derived parameter that reported to be a valuable prognostic factor in cancer patients. Herein, we aimed to identify a prognostic gene signature associated with glucose uptake for breast cancer patients after RT by leveraging the mRNA expression profiling on public datasets. The glucose uptake signature was constructed using the single sample gene set enrichment analysis (ssGSEA) algorithm and evaluated in GSE21217 where SUVmax value was measured by PET-CT directly. The prognostic value was validated in three post-RT breast cancer cohorts (GSE103744, NKI, and FUSCC databases). The patients were stratified into glucose uptake signature score-high and low groups. Patients with a higher score had worse survival than those with a lower score. Mechanistically, the glucose uptake signature was calculated in each cell type of a single-cell RNA-seq database from five breast cancer patients. Glucose uptake signature score was significantly elevated in the malignant epithelial cells compared with normal ones. The immunosuppression markers including PDCD1, TIGIT, LAG3, and HAVCR2 were significantly upregulated in the T cells bearing a high glucose uptake signature score. Collectively, our results demonstrated the potential prognostic value of a glucose uptake signature in the post-RT breast cancer patients.

Breast cancer has become the most common malignant tumor worldwide. However, the survival rate of breast cancer patients in China is 8% lower compared to that in European and American countries. Insufficient screening coverage and low rate of early detection are key problems. Therefore, it is imperative to develop a set of guidelines for breast cancer screening, early diagnosis, and treatment strategies suitable for Chinese women. The National Health Commission, the National Cancer Center, and the National Cancer Quality Control Center collectively organized a committee of specialists with multidisciplinary backgrounds in breast surgery, oncology, radiotherapy, diagnostic imaging, ultrasound, pathology, epidemiology, and health economics. The committee collectively published ''China Breast Cancer Screening, Early Diagnosis and Treatment Specification'', in which the committee outlined a set of strategies of breast cancer screening, early diagnosis, and treatment suitable for China's national conditions. The strategies were formulated based on clinical experience in breast cancer prevention and treatment, characteristics of breast cancer patients in China, and socioeconomic conditions. The purpose of this article is to provide an interpretation of the above guidelines as a reference for breast cancer screening.

BackgroundNeoadjuvant chemotherapy (NAC) has evolved significantly and has been widely accepted for downstaging disease in early-stage and locally advanced breast cancer patients. Since the optimal surgical intervention for patients receiving NAC remains controversial, we aim to investigate the survival outcome of patients treated with different surgical management.MethodsA retrospective, nested case-control study was conducted in patients with invasive breast cancer that underwent NAC at Fudan University Shanghai Cancer Center from January 2010 to June 2019. Based on surgical intervention, patients were divided into mastectomy and breast conservation groups. Patients were matched on age at diagnosis, menopausal status, the year of the surgery, post neoadjuvant therapy pathological tumor (ypT) stage, post neoadjuvant therapy pathological node (ypN) stage, molecular subtypes, and axillary surgery by propensity score matching.ResultsA total of 2080 patients were enrolled in this study. Among them, 1819 (87.5%) patients were categorized as mastectomy group, and 261 (12.5%) patients were classed as breast conservation group. Over 9-years of research, the proportion of breast conservation steadily increased in patients after NAC. Data showed that younger (P

Background Despite the success of HER2-targeted therapy in achieving prolonged survival in approximately 50% of treated individuals, treatment resistance is still an important challenge for HER2+ breast cancer (BC) patients. The influence of both adaptive and innate immune responses on the therapeutic outcomes of HER2+BC patients has been extensively demonstrated.Methods Long non-coding RNAs expressed in non-pathological complete response (pCR) HER2 positive BC were screened and validated by RNA-seq. Survival analysis were made by Kaplan-Meier method. Cell death assay and proliferation assay were performed to confirm the phenotype of LINC00624. RT-qPCR and western blot were used to assay the IFN response. Xenograft mouse model were used for in vivo confirmation of anti-neu treatment resistance. RNA pull-down and immunoblot were used to confirm the interaction of ADAR1 and LINC00624. ADAR1 recombinant protein were purified from baculovirus expression system. B16-OVA cells were used to study antigen presentation both in vitro and in vivo. Flow cytometry was used to determine the tumor infiltrated immune cells of xenograft model. Antisense oligonucleotides (ASOs) were used for in vivo treatment.Results In this study, we found that LINC00624 blocked the antitumor effect of HER2- targeted therapy both in vitro and in vivo by inhibiting type I interferon (IFN) pathway activation. The double-stranded RNA-like structure of LINC00624 can bind and be edited by the adenosine (A) to inosine (I) RNA-editing enzyme adenosine deaminase RNA specific 1 (ADAR1), and this editing has been shown to release the growth inhibition and attenuate the innate immune response caused by the IFN response. Notably, LINC00624 promoted the stabilization of ADAR1 by inhibiting its ubiquitination-induced degradation triggered by β-TrCP. In contrast, LINC00624 inhibited major histocompatibility complex (MHC) class I antigen presentation and limited CD8+T cell infiltration in the cancer microenvironment, resulting in immune checkpoint blockade inhibition and anti-HER2 treatment resistance mediated through ADAR1.Conclusions In summary, these results suggest that LINC00624 is a cancer immunosuppressive lncRNA and targeting LINC00624 through ASOs in tumors expressing high levels of LINC00624 has great therapeutic potential in future clinical applications.

Background: Breast cancer (BC) is the most common malignant tumour, and its heterogeneity is one of its major characteristics. N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing constitute the four most common adenosine-associated RNA modifications and represent the most typical and critical forms of epigenetic regulation contributing to the immunoinflammatory response, tumorigenesis and tumour heterogeneity. However, the cross-talk and potential combined profiles of these RNA-modified proteins (RMPs) in multivariate prognostic patterns of BC remain unknown.Methods: A total of 48 published RMPs were analysed and found to display significant expression alterations and genomic mutation rates between tumour and normal tissues in the TCGA-BRCA cohort. Data from 4188 BC patients with clinical outcomes were downloaded from the Gene Expression Omnibus (GEO), the Cancer Genome Atlas (TCGA), and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), normalized and merged into one cohort. The prognostic value and interconnections of these RMPs were also studied. The four prognosis-related genes (PRGs) with the greatest prognostic value were then selected to construct diverse RMP-associated prognostic models through univariate Cox (uniCox) regression analysis, differential expression analysis, Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox (multiCox) regression. Alterations in biological functional pathways, genomic mutations, immune infiltrations, RNAss scores and drug sensitivities among different models, as well as their prognostic value, were then explored.Results: Utilizing a large number of samples and a comprehensive set of genes contributing to adenosine-associated RNA modification, our study revealed the joint potential bio-functions and underlying features of these diverse RMPs and provided effective models (PRG clusters, gene clusters and the risk model) for predicting the clinical outcomes of BC. The individuals with higher risk scores showed poor prognoses, cell cycle function enrichment, upregulation of stemness scores, higher tumour mutation burdens (TMBs), immune activation and specific drug resistance. This work highlights the significance of comprehensively examining post-transcriptional RNA modification genes.Conclusion: Here, we designed and verified an advanced forecasting model to reveal the underlying links between BC and RMPs and precisely predict the clinical outcomes of multivariate prognostic patterns for individuals.

An urban agglomeration is the engine of regional and national economic growth, but also causes many ecological and environmental issues that emerge from massive land changes. In this study, the spatiotemporal evolution of an urban agglomeration was quantified and its impacts on the urban and regional landscape patterns were evaluated. It showed that the urbanized land area of the Pearl River Delta Urban Agglomeration (PRDUA) in China nearly quadrupled, having linearly increased from 1819.8 km2 to 7092.2 km2 between 1985 and 2015. The average annual growth rate presented a bimodal wave-like pattern through time, indicating that the PRDUA has witnessed two rounds of the urbanization process. The growth modes (e.g., leapfrog, edge-expansion, infilling) were detected and they exhibited co-existing but alternating dominating patterns during urbanization, demonstrating that the spatiotemporal evolution of the urban development of the PRDUA follows the “spiral diffusion-coalescence” hypothesis. The morphology of the PRDUA presented an alternating dispersal-compact pattern over time. The city-level and regional-level landscape patterns changed synchronously with the spatiotemporal evolution of the PRDUA over time. The urbanization of the PRDUA increased both the complexity and aggregation of the landscape, but also resulted in an increasing fragmentation and decreasing connectivity of the natural landscape in the Pearl River Delta region. These findings are helpful for better understanding how urban agglomerations evolve and in providing insights for regional urban planning and sustainable land management.

Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late‐stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2‐mediated glycolysis and angiogenesis through multiple protein–protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF‐κB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF‐κB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.

BackgroundBreast cancer is one of the leading causes of cancer-related death among women, and the pathological status of axillary lymph nodes is an important predictor of prognosis. However, the mechanism involved in this early stage of metastasis remains largely unknown.MethodsMicroarray analysis was used to carry out differential genomics analyses between matched pairs of metastatic sentinel lymph node tissues and breast primary tumors. The CRISPR/Cas9 gene editing system was used for in vivo screening by transplanting a loss-of-function cell pool into immunocompromised mice. MAGeCK was used to analyze the screening results. Survival analysis was performed via the Kaplan–Meier method. Cell proliferation, wound healing, migration and invasion assays were performed to confirm the phenotype. A tail vein model and subcutaneous xenotransplanted tumor model were used for the in vivo study. The relationship between coiled-coil domain containing 102B (CCDC102B) and receptor for activated C kinase 1 (RACK1) was examined using coimmunoprecipitation, mass spectrometry, nuclear protein extraction and immunofluorescence assays. The primary biological functions and pathways related to CCDC102B were enriched by RNA sequencing.ResultsWe identified CCDC102B through screening and found that it was significantly upregulated in metastatic lesions in lymph nodes compared to matched primary tumors. Increased expression of CCDC102B promoted breast cancer metastasis in vitro and in vivo. Additionally, high expression of CCDC102B was correlated with poor clinical outcomes in breast cancer patients. We further identified that CCDC102B was stabilized by the loss of RACK1, a protein negatively correlated with breast cancer metastasis. Mechanistically, we found that RACK1 promoted CCDC102B lysosomal degradation by mediating chaperone-mediated autophagy (CMA). The aggressive behavior of CCDC102B in breast cancer cells could be reversed by the expression of RACK1. Moreover, CCDC102B was correlated with the significant enrichment of NF-κB pathway components. Overexpressing CCDC102B led to less interaction between RACK1 and IKKa. Thus, CCDC102B positively regulates the NF−κB pathway by interacting with RACK1.ConclusionTaken together, our findings uncover a novel role of CCDC102B in breast cancer metastasis. CCDC102B serves as a potential metastasis promoter by regulating the activation of the NF-κB pathway and can be degraded by RACK1 via CMA.

BackgroundMitoxantrone hydrochloride injection for tracing (MHI), a new strategy to identify lymph nodes, has not been tested for axillary node staging in breast cancer. This multicenter, self-controlled, non-inferiority trial aimed to evaluate MHI’s efficacy and safety in sentinel lymph node biopsy (SLNB).MethodsThe trial was conducted across seven hospitals from December 2019 to December 2020. Patients with early-stage breast cancer received MHI and technetium-99m (99mTc) during the surgery. Sentinel node detection rates were compared between MHI and 99mTc to evaluate non-inferiority and concordance. Non-inferiority was valid if the lower limit of the 95% CI of sentinel node relative detection rate difference was ≥−5%.ResultsSLN relative detection rate of MHI was 97.31% (362/372). Of the SLNs, 79.69% (871/1093) were co-detected by both tracers. Of the patients, 4.13% (16/387) had adverse events and recovered during the follow-up.ConclusionsMHI is a lymphatic tracer with comparable efficacy to radionuclides and can be used alone or in combination with radioactive substances for SLNB.Clinical Trial Registrationhttp://www.chinadrugtrials.org.cn, CTR20192435.

BackgroundCompared with older patients, young women with breast cancer (YWBCs) have a poorer prognosis and a higher risk of recurrence. Ages ≤35 years are independent risk factors for local recurrence of breast cancer. Surgery is the most important local treatment for YWBC, and there is still a lack of prospective studies comparing surgical options for recurrence and survival. We retrospectively compared the effects of surgical options on disease-free survival (DFS) and overall survival (OS) of YWBC at Fudan University Shanghai Cancer Center (FUSCC).MethodsYWBCs (age ≤35 years) who underwent surgery at FUSCC between 2008 and 2016 were retrospectively analyzed and divided into three groups according to surgical options: 1) breast-conserving surgery (BCS), 2) mastectomy alone (M), and 3) mastectomy with reconstruction (RECON). The DFS and OS outcome rates from the three surgical options were compared using the Kaplan–Meier method and Cox regression model. Propensity score matching (PSM) was also used to balance the baseline characteristics to eliminate selection bias.ResultsA total of 1,520 YWBCs were enrolled with a median follow-up of 5.1 years, including 524 patients (34.5%) who underwent BCS, 676 patients (44.5%) who underwent M, and 320 patients (21.1%) who underwent RECON. The 5-year DFS rates were 96%, 87%, and 93%, respectively (P < 0.001); the 5-year OS rates were 98%, 94%, and 97%, respectively (P = 0.002). Multivariate Cox analysis showed that DFS and OS were significantly improved in patients undergoing BCS compared with those undergoing M, with hazard ratios (HR) of 0.448 (95% CI 0.276–0.728; P = 0.001) and 0.405 (95% CI 0.206–0.797, P = 0.009), respectively. After PSM, DFS and OS rates were significantly improved in patients undergoing BCS compared to patients undergoing M (DFS, P = 0.001; OS, P = 0.009); RECON was also improved compared to patients undergoing M in terms of DFS and OS, but the difference was not statistically significant (DFS, P = 0.164; OS, P = 0.130).ConclusionsThe surgical options were independent factors affecting DFS and OS in YWBC, and the DFS and OS rates were significantly improved in the BCS group compared to those in the M group. BCS is preferred for early YWBC, and RECON is the best option for remodeling the body images of YWBC who do not have breast-conserving conditions.

Genotoxic agents have been shown to activate the Wnt/β-catenin signaling but the underlying mechanism remains unclear. Here, the authors show that upon DNA damage, the deubiquitinase OTULIN activates Wnt/β-catenin signaling by inhibiting linear ubiquitination, K48-linked polyubiquitination, and proteasomal degradation of β-catenin.

Liver and liver tumor segmentation provides vital biomarkers for surgical planning and hepatic diagnosis. In this paper, we propose and validate a novel level-set method integrating an enhanced edge indicator and an automatically derived initial curve for CT based liver tumor segmentation. At the preprocessing step, the CT image intensity values were truncated to lie in a fixed range to enhance the image contrast surrounding liver and liver tumor. To remove non-liver tissues for subsequent tumor segmentation, liver was firstly segmented using two convolutional neural networks in a coarse-to-fine manner. A 2D slice-based U-net was used to roughly localize the liver and a 3D patch-based fully convolutional network was used to refine the liver segmentation as well as to roughly localize the liver tumor. A novel level-set method was then presented to further refine the tumor segmentation. Specifically, the probabilistic distribution of the liver tumor was estimated using unsupervised fuzzy c-means clustering, which was then utilized to enhance the edge-detector used in level-set. Effectiveness of the proposed pipeline was validated on two publicly-available datasets. Experimental results identified the superior segmentation performance of the proposed pipeline over state-of-the-art methods.

Abstract Background The majority of breast cancer patients die of metastasis rather than primary tumors, whereas the molecular mechanisms orchestrating cancer metastasis remains poorly understood. Long noncoding RNAs (lncRNA) have been shown to regulate cancer occurrence and progression. However, the lncRNAs that drive metastasis in cancer patients and their underlying mechanisms are still largely unknown. Methods lncRNAs highly expressed in metastatic lymph nodes were identified by microarray. Survival analysis were made by Kaplan-Meier method. Cell proliferation, migration, and invasion assay was performed to confirm the phenotype of LINC02273. Tail vein model and mammary fat pad model were used for in vivo study. RNA pull-down and RIP assay were used to confirm the interaction of hnRNPL and LINC02273. Chromatin isolation by RNA purification followed by sequencing (ChIRP-seq), RNA-seq, ChIP-seq, and luciferase reporter assay reveal hnRNPL-LINC02273 regulates AGR2. Antisense oligonucleotides were used for in vivo treatment. Results We identified a novel long noncoding RNA LINC02273, whose expression was significantly elevated in metastatic lesions compared to the primary tumors, by genetic screen of matched tumor samples. Increased LINC02273 promoted breast cancer metastasis in vitro and in vivo. We further showed that LINC02273 was stabilized by hnRNPL, a protein increased in metastatic lesions, in breast cancer cells. Mechanistically, hnRNPL-LINC02273 formed a complex which activated AGR2 transcription and promoted cancer metastasis. The recruitment of hnRNPL-LINC02273 complex to AGR2 promoter region epigenetically upregulated AGR2 by augmenting local H3K4me3 and H3K27ac levels. Combination of AGR2 and LINC02273 was an independent prognostic factor for predicting breast cancer patient survival. Moreover, our data revealed that LINC02273-targeting antisense oligonucleotides (ASO) substantially inhibited breast cancer metastasis in vivo. Conclusions Our findings uncover a key role of LINC02273-hnRNPL-AGR2 axis in breast cancer metastasis and provide potential novel therapeutic targets for metastatic breast cancer intervention.

Abstract Background Patients diagnosed with ductal carcinoma in situ (DCIS) by core needle biopsy (CNB) have a great chance of upstaging to invasive cancer. Positive axillary status can be found in these patients. This study sought to identify clinicopathological factors associated with upstaging and axillary metastasis in patients preoperatively diagnosed with DCIS by CNB. Materials and Methods This study identified 604 patients (cT1‐3N0M0) with preoperative diagnosis of pure DCIS by CNB who had undergone axillary evaluation from August 2006 to December 2015 at Fudan University Shanghai Cancer Center (FUSCC). Predictors of upstaging and axillary lymph nodes metastasis were analyzed, respectively. Results Of all 604 patients, 121 (20.03%) and 193 (31.95%) patients were upstaged to DCIS with microinvasion (DCISM) and invasive breast cancer (IBC). Positive axillary lymph nodes were identified in 41 (6.79%) patients. Predictors of upstaging included tumor size on ultrasonography (>2 cm) (OR 1.786, P = .002) and ER+HER2+ status (OR 1.874, P = .022) in multivariate analysis. Factors associated with axillary lymph nodes metastasis included tumor size on pathology (OR 2.336, P = .038) and number of lesions (OR 3.354, P = .039) in multivariate analysis. In addition, upstaging on final pathology had a significant influence on axillary lymph nodes status (P 2 cm), multifocal lesions or ER+HER2+ status. Despite of a 51.98% upstaging rate, the rate of axillary metastasis in these patients was relatively low, supporting the omission of axillary evaluation in selected patients with low risk of upstaging or axillary metastasis.

Background: New biomarker combinations have been increasingly developed to improve the precision of current diagnostic and therapeutic modalities. Recently, researchers have found that tumor cells are more vulnerable to ferroptosis. Furthermore, ferroptosis-related genes (FRG) are promising therapeutic targets in breast cancer patients. Therefore, this study aimed to identify FRG that could predict disease-specific survival (DSS) in breast cancer patients.Methods: Gene expression matrix and clinical data were downloaded from public databases. We included 960, 1,900, and 234 patients from the TCGA, METABRIC, and GSE3494 cohorts, respectively. Data for FRG were downloaded from the FerrDb website. Differential expression of FRG was analyzed by comparing the tumors with adjacent normal tissues. Univariate Cox analysis of DSS was performed to identify prognostic FRG. The TCGA-BRCA cohort was used to generate a nine-gene panel with the LASSO cox regression. The METABRIC and GSE3494 cohorts were used to validate the panel. The panel’s median cut-off value was used to divide the patients into high- or low-risk subgroups. Analyses of immune microenvironment, functional pathways, and clinical correlation were conducted via GO and KEGG analyses to determine the differences between the two subgroups.Results: The DSS of the low-risk subgroup was longer than that of the high-risk subgroup. The panel’s predictive ability was confirmed by ROC curves (TCGA cohort AUC values were 0.806, 0.695, and 0.669 for 2, 3, and 5 years respectively, and the METABRIC cohort AUC values were 0.706, 0.734, and 0.7, respectively for the same periods). The panel was an independent DSS prognostic indicator in the Cox regression analyses. (TCGA cohort: HR = 3.51, 95% CI = 1.792–6.875, p < 0.001; METABRIC cohort: HR = 1.76, 95% CI = 1.283–2.413, p < 0.001). Immune-related pathways were enriched in the high-risk subgroup. The two subgroups that were stratified by the nine-gene panel were also associated with histology type, tumor grade, TNM stage, and Her2-positive and TNBC subtypes. The patients in the high-risk subgroup, whose CTLA4 and PD-1 statuses were both positive or negative, demonstrated a substantial clinical benefit from combination therapy with anti-CTLA4 and anti-PD-1.Conclusion: The new gene panel consisting of nine FRG may be used to assess the prognosis and immune status of patients with breast cancer. A precise therapeutic approach can also be possible with risk stratification.

This paper describes a method for determining the initiation and unstable toughness of fully graded concrete of arbitrary specimen size. The method first predicts the initiation and peak loads of concrete specimens of any size, as well as crack length-to-height ratios based on the fracture test results of concrete specimens with limited sizes or crack length-to-height ratios. Then, combined with the fracture extreme theory, the fracture toughness of concrete with varying size or crack length-to-height ratios is determined. Finally, in order to verify the applicability of the method, it is used to calculate the fracture toughness of small aggregate concrete and fully graded concrete with different sizes or crack length-to-height ratios, and its prediction accuracy is evaluated through indices such as mean absolute percentage error, root mean square error and reliability index a15. The results show that the proposed method can meet the needs of practical engineering applications and can provide theoretical basis for the optimization of the fracture test method of fully graded concrete and the determination of fracture parameters in crack stability or propagation analysis.

BackgroundLncRNAs have been shown to play critical roles in regulating tumorigenesis and tumor progression. Using LncRNAs to predict prognosis and therapeutic response to cancer treatment has been caused for concern, but the predictive value of lncRNAs remains to be explored and underlying mechanisms have not been completely understood.MethodsThe Linc01315 expression level was detected in 282 breast cancer tissues by using quantitative RT-PCR. The association between Linc01315 expression level and clinicopathological features of these breast cancer patients was further analyzed. Multiple regression analysis was used to evaluate Linc01315 predictive value of patients’ prognosis.ResultsOur study revealed that Linc01315 expression level was significantly correlated with vessel invasion (P = 0.028) and tumor subtype (P = 0.039). The Kaplan–Meier survival curves demonstrated that patients with lower Linc01315 expression level had significantly longer disease free survival (DFS) (P = 0.002) and overall survival (OS) (P=0.019). Multiple regression analysis showed that Linc01315 level could be an independent predictive factor for DFS (hazards ratio = 0.613, 95% confidence interval = 0.375-1.003; P = 0.049) and OS (hazards ratio = 0.439, 95% confidence interval = 0.228-0.845; P = 0.014). Further analysis showed that low Linc01315 level patients with endocrine therapy could benefit patients DFS (P=0.037) and OS (P=0.025).ConclusionOur results demonstrate that Linc01315 expression level is significantly correlated with breast cancer patients’ prognosis. Linc01315 may represent an independent prognostic marker and therapeutic target in breast cancer.

Objectives: Arterial hyperoxia is reportedly a risk factor for poor outcomes in patients with hemorrhagic brain injury (HBI). However, most previous studies have only evaluated the effects of hyperoxia using static oxygen partial pressure (PaO2) values. This study aimed to investigate the association between overall dynamic oxygenation status and HBI outcomes, using longitudinal PaO2 data.Methods: Data were extracted from the Medical Information Mart for Intensive Care III database. Longitudinal PaO2 data obtained within 72 h of admission to an intensive care unit were analyzed, using a group-based trajectory approach. In-hospital mortality was used as the primary outcomes. Multivariable logistic models were used to explore the association between PaO2 trajectory and outcomes.Results: Data of 2,028 patients with HBI were analyzed. Three PaO2 trajectory types were identified: Traj-1 (mild hyperoxia), Traj-2 (transient severe hyperoxia), and Traj-3 (persistent severe hyperoxia). The initial and maximum PaO2 of patients with Traj-2 and Traj-3 were similar and significantly higher than those of patients with Traj-1. However, PaO2 in patients with Traj-2 decreased more rapidly than in patients with Traj-3. The crude in-hospital mortality was the lowest for patients with Traj-1 and highest for patients with Traj-3 (365/1,303, 209/640, and 43/85 for Traj-1, Traj-2, and Traj-3, respectively; p < 0.001), and the mean Glasgow Coma Scale score at discharge (GCSdis) was highest for patients with Traj-1 and lowest in patients with Traj-3 (13 [7–15], 11 [6–15], and 7 [3–14] for Traj-1, Traj-2, and Traj-3, respectively; p < 0.001). The multivariable model revealed that the risk of death was higher in patients with Traj-3 than in patients with Traj-1 (odds ratio [OR]: 3.3, 95% confidence interval [CI]: 1.9–5.8) but similar for patients with Traj-1 and Traj-2. Similarly, the logistic analysis indicated the worst neurological outcomes in patients with Traj-3 (OR: 3.6, 95% CI: 2.0–6.4, relative to Traj-1), but similar neurological outcomes for patients in Traj-1 and Traj-2.Conclusion: Persistent, but not transient severe arterial hyperoxia, was associated with poor outcome in patients with HBI.

BackgroundThe genomic tests such as the MammaPrint and Oncotype DX test are being gradually applied for hormone receptor positive/HER-2 negative (HR+/HER2-) breast cancer patients with up to three positive axillary lymph nodes (ALNs). The first results from RxPONDER trial suggested that Oncotype DX could be applied to patients with 1-2 positive sentinel lymph nodes (SLNs) without axillary lymph node dissection (ALND), which constituted 37.4% of the intent-to-treat population. However, there was no distinctive research on how to apply genomic tests precisely to HR+/HER2- patients with 1-2 positive SLNs without ALND. The purpose was to construct a nomogram using the multi-center retrospective data to predict precisely which HR+/HER2- candidates with 1-2 positive SLNs could be subjected to genomic tests (≤ 3 positive lymph nodes).MethodsWe conducted a retrospective analysis of 18,600 patients with stage I-III breast cancer patients treated with sentinel lymph node biopsy (SLNB) in Shandong Cancer Hospital, Fudan University Shanghai Cancer Center, and West China Hospital. The univariate and multivariate logistic regression analysis was conducted to identify the independent predictive factors of having ≤ 3 positive nodes among patients with 1-2 positive SLNs. A nomogram was developed based on variables in the final model with p

As global warming progresses, heat and hypoxia are gradually becoming important factors threatening the survival, reproduction, and development of marine organisms. To determine the effect of heat and hypoxia on Apostichopus japonicus, whole genome methylation of the respiratory tree was determined under heat, hypoxia, and heat-hypoxia conditions [designed as heat stress treatment (HT), hypoxia treatment (LO), and heat-hypoxia combined treatment (HL) groups]. The number of differentially methylated regions (DMRs) under three treatments was determined based on the Venn diagram. The network of the DMRs associated with promoters that were co-existed under the three conditions showed that circadian rhythm was involved based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Circadian rhythm-related genes, CRY1a, CRY1b, CLC, and TIM, decreased in LO and HL groups, while CRY1a, CRY1b, and BMAL1 increased in the HT group. Bisulfite sequencing PCR (BSP) showed that the methylation levels of CpG island regions in the promoters of CRY1a and CRY1b were upregulated in HT, LO, and HL groups, leading to the decreased promoter activity of CRY1a and CRY1b. RNAi of CRY1a and CRY1b led to increased enzyme activities of two energy-related enzymes, pyruvate kinase (PK) catalyzing the rate-limiting step in glycolysis, and ATPase hydrolyzing ATP to ADP, which were also increased under the three tested conditions. Thus, it was concluded that A. japonicus may respond to the heat, hypoxia, and heat-hypoxia stresses via the DNA methylation of heat, hypoxia, and heat-hypoxia stresses via the DNA methylation of CpG islands of circadian rhythm-related genes, which increased the activity of energy-related enzymes.

BackgroundLoco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis.MethodsTo delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype.ResultsWith a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery.ConclusionsLRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

The application of organic fertilizer has been one of the most important agricultural practices to increase tea plant productivity. However, a single organic fertilizer alone could not match the nutrient requirements of tea plant. According to the nutrient demand of tea plant, tea-specific fertilizer with an appropriate nutrient ratio in combination with organic fertilizer would be an appropriate way. A four-year field experiment was conducted to characterize the sensory quality of green tea subjected to four different fertilization treatments, i.e., tea-specific fertilizer (N-P2O5-K2O: 18-8-12) + urea + colza cake, tea-specific fertilizer + urea + livestock waste compost, and tea-specific fertilizer + urea, combined tea-specific fertilizer (referred to as M1, M2, and M3, respectively); nonfertilizing (CK) served as control. The fertilizer formulated specifically for tea could enhance the taste qualities of green tea, such as water extract, caffeine, tea polyphenol, EGCG, and ECG. However, the effect of this fertilizer on enhancing the aroma level of green tea was weaker than that of the application of tea-specific fertilizer combined with organic fertilizer, whereby this combined fertilization significantly improved the concentration of green tea aroma compounds, such as D-limonene, cis-jasmone, nonanal, linalool, cis-3-hexenyl hexanoate, and cis-3-hexenyl benzoate. This study provides a theoretical basis for judicious fertilization by combining tea-specific fertilizer and organic fertilizer in tea orchards.

BackgroundTrastuzumab shows excellent benefits for HER2+ breast cancer patients, although 20% treated remain unresponsive. We conducted a retrospective cohort study to optimize neoadjuvant chemotherapy and trastuzumab treatment in HER2+ breast cancer patients.MethodsSix hundred patients were analyzed to identify clinical characteristics of those not achieving a pathological complete response (pCR) to develop a clinical predictive model. Available RNA sequence data was also reviewed to develop a genetic model for pCR.ResultsThe pCR rate was 39.8% and pCR was associated with superior disease free survival and overall survival. ER negativity and PR negativity, higher HER2 IHC scores, higher Ki-67, and trastuzumab use were associated with improved pCR. Weekly paclitaxel and carboplatin had the highest pCR rate (46.70%) and the anthracycline+taxanes regimen had the lowest rate (11.11%). Four published GEO datasets were analyzed and a 10-gene model and immune signature for pCR were developed. Non-pCR patients were ER+PR+ and had a lower immune signature and gene model score. Hormone receptor status and immune signatures were independent predictive factors of pCR.ConclusionHormone receptor status and a 10-gene model could predict pCR independently and may be applied for patient selection and drug effectiveness optimization.

Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

Abstract Background Long non-coding RNAs play an important role in breast cancer. Even with adjuvant hormone therapy, patients with estrogen receptor positive breast cancer can present with recurrences and distant metastases. We investigated whether the expression of a novel long non-coding RNA LINC00309 can predict the outcome of breast cancer, especially for hormone-receptor positive patients. Methods This retrospective study collected 290 breast cancer patients including 161 patients with hormone-positive. qPCR was performed to detect the expression of LINC00309. Kaplan–Meier and Cox risk proportion model were applied to disclose the function of LINC00309 for breast cancer prognosis. Results LINC00309 high expression was an independent predictor for worse disease-free survival (HR = 2.127; 95% CI 1.074–4.212; p = 0.030) and associated with a shorter disease-free survival (p = 0.027), especially in hormone-positive breast cancer patients (p = 0.001). Also LINC00309 high expression was associated with a shorter disease-free survival both in selective estrogen receptor modulator related hormone therapy (p = 0.025) and aromatase inhibitors related hormone therapy (p = 0.048). Moreover, LINC00309 was an independent predictor of worse disease-free survival in hormone-receptor positive breast cancer patients on univariate (HR = 4.505; 95% CI 1.722–11.785; p = 0.002) and multivariate (HR = 4.159; 95% CI 1.537–11.251; p = 0.005) analyses. Conclusion In breast cancer, Linc00309 is significantly associated with poor prognosis and may represent a new marker of prognosis.

Objective Patients preoperatively diagnosed with ductal carcinoma in situ (DCIS) by core needle biopsy (CNB) exhibit a significant risk for upstaging on final pathology, which leads to major concerns of whether axillary staging is required at the primary operation. The present study aimed to identify clinicopathological factors associated with upstaging in patients preoperatively diagnosed with DCIS by CNB.Methods The present study enrolled 604 patients (cN0M0) with a preoperative diagnosis of pure DCIS by CNB, who underwent axillary staging between August 2006 and December 2015, at Fudan University Shanghai Cancer Center (Shanghai, China). Predictive factors of upstaging were analyzed retrospectively.Results Of the 604 patients, 20.03% (n = 121) and 31.95% (n = 193) were upstaged to DCIS with microinvasion (DCISM) and invasive breast cancer (IBC) on final pathology, respectively. Larger tumor size on ultrasonography (> 2 cm) was independently associated with upstaging [odds ratio (OR) 1.558, P = 0.014]. Additionally, patients in lower breast imaging reporting and data system (BI-RADS) categories were less likely to be upstaged (4B vs. 5: OR 0.435, P = 0.002; 4C vs. 5: OR 0.502, P = 0.001). Overall, axillary metastasis occurred in 6.79% (n = 41) of patients. Among patients with axillary metastasis, 1.38% (4/290), 3.31% (4/121) and 17.10% (33/193) were in the DCIS, DCISM, and IBC groups, respectively.Conclusions For patients initially diagnosed with DCIS by CNB, larger tumor size on ultrasonography (> 2 cm) and higher BI-RADS category were independent predictive factors of upstaging on final pathology. Thus, axillary staging in patients with smaller tumor sizes and lower BI-RADS category may be omitted, with little downstream risk for upstaging.

Abstract Background Accumulating studies have focused on the oncogenic roles of the newly identified lncRNAs in human cancers. The aim of this study was to examine the expression pattern of Linc00959 in BC and to evaluate its biological role and clinical significance in prediction of prognosis. Methods Expression of Linc00959 was detected in 290 BC tissues by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We analyzed the relationship between Linc00959 expression and clinic pathological features of BC patients. The correlation was calculated by SPSS software. Results Our results revealed that Linc00959 expression was correlated with ER status (p = 0.005), PR status (p = 0.036), Ki67 (p = 0.025) and HER2 status (p = 0.009). The Kaplan–Meier survival curves indicated that the overall survival (OS) (p = 0.022) and relapse-free survival (RFS) (p = 0.002) were significantly poor in high Linc00959 expression BC patients (p = 0.023). Furthermore, the survival analysis by Cox regression showed that Linc00959 served as an independent prognostic marker in breast cancer (p = 0.004). Conclusion Our studies indicate that Linc00959 is significantly associated with poor prognosis and may represent a new marker of prognosis in breast cancer.